This proposal is designed to characterize the modulation of voltage-gated sodium and calcium currents by NMDA in retinal horizontal cells, to explore the mechanism by which modulation occurs and to look at functional implications of NMDA in the distal retina. The role of NMDA receptors in brain has been intensely examined in relation to long-term potentiation, excitotoxicity and neural development and plasticity. However, in the distal retina, the role of the NMDA receptor is unclear. Based on preliminary data, the model that will be tested is that activation of the NMDA receptor in horizontal cells results in calcium influx through the NMDA channel and CICR from caffeine-sensitive intracellular stores. NMDA-induced inhibition of the voltage-sensitive sodium and calcium conductance is dependent on this and the activation of the calcium binding protein, calmodulin. [unreadable] [unreadable] The type of information encoded by the light response includes details pertaining to stimulus brightness, neurotransmitter gain efficacy, contrast detection and the light and dark condition of the retina. Therefore, it is essential to understand how voltage-gated channels contribute to the encoding of this visual information before adequate artificial retinas can be developed for clinical purposes and before treatments for diseases that affect the retina, such as Parkinson's, can be effective. The three specific aims outlined in this proposal are designed to: I) to test the hypothesis that NMDA receptor activation inhibits both the voltage-gated sodium and voltage-gated calcium currents found in catfish cone horizontal cells, II) to test the hypothesis that NMDA contributes to formation of the light response and the dark resting membrane potential in catfish cone horizontal cells, and III) to test the hypothesis that calcium dependent signaling pathways link activation of NMDA receptors to inhibition of the voltage-gated sodium and calcium channels in catfish cone horizontal cells. These specific aims will be carried out using a multidisciplinary approach combining electrophysiological, pharmacological and immunocytochemical and calcium imaging techniques. Results obtained using isolated cells and a retinal slice preparation will contribute significantly to the long-range goal of this research, which is to understand how voltage-gated channels affect visual information conveyed through the vertebrate retina. [unreadable] [unreadable]